The central nervous system and the immune system are closely interrelated. Both animal models and human studies have shown that stress interferes with immune regulation. We have earlier reported that major depression is associated with a reduction in Natural Killer (NK) cell activity, a parameter of cellular immunity. Our data also suggest that cortisol levels, which are increased in many patients with major depression, cannot solely explain the immunosuppression observed in depressed patients. In this application, we propose to extend the characterization of immune dysregulation in patients with major depression and to study possible mechanisms of immunosuppression in these patients. First, we will conduct immunological studies to explore mechanisms of immunosuppression at the cellular and molecular levels. These include lymphocyte surface marker analyses, studies of cytotoxic and suppressor cell activities, assays of target binding and recycling capacity, and lymphokine production. Second, we will conduct neuroendocrine studies focusing on the hypothalamic- pituitary-adrenal (HPA) axis to 1) explore possible correlations between ACTH beta-endorphin and/or cortisol secretion and specific immune measures over a 24-hour period; and 2) assess the effects of ovine Corticotropin Releasing Hormone (oCRH) given intravenously on neuroendocrine secretion and immune function. Last, we will compare neuroendocrine-immune interactions in three groups of subjects with varying levels of HPA activation: 1) depressed patients; 2) patients with Cushing's syndrome; and 3) normal controls. A better understanding of immune regulation in patients with depressive illness and Cushing's syndrome will enhance our knowledge of the interactions between the brain and the immune system and the possible role that HPA axis activity plays in these interactions.